Limonoids from .

Eighteen new limonoids, including eight methyl angolensates (-) and 10 cipadesins (-), were isolated from the leaves of . Their structures were characterized by means of spectroscopic data analyses, single-crystal X-ray diffraction, and quantum chemistry computational methods. The C-6 configurations in those compounds possessing a C-6 hydroxy group were all assigned as regardless of the magnitude of , and the C-2' configuration in those bearing a 2-methylbutyryl residue was defined by single-crystal X-ray diffraction and NMR data.

Functional annotation of serine hydrolases in the asexual erythrocytic stage of Plasmodium falciparum.

Enzymes of the serine hydrolase superfamily are ubiquitous, highly versatile catalysts that mediate a wide variety of metabolic reactions in eukaryotic cells, while also being amenable to selective inhibition. We have employed a fluorophosphonate-based affinity capture probe and mass spectrometry to explore the expression profile and metabolic roles of the 56-member P. falciparum serine hydrolase superfamily in the asexual erythrocytic stage of P.

Isolation and characterization of antiplasmodial constituents from the marine sponge Coscinoderma sp.

Six known compounds, namely two halisulfates 1 and 2 and four epidioxy sterols 3-6, were isolated from the marine sponge Coscinoderma sp. The structures of these compounds were confirmed by nuclear magnetic resonance (1H and 13C NMR) spectroscopy, and their antiplasmodial activities were determined against the chloroquine-resistant Dd2 strain of Plasmodium falciparum. The epidioxy steroids 3-6 all showed moderate to weak antiplasmodial activity, with IC50 values of 2.

Evidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporter.

Plasmodium falciparum multidrug resistance constitutes a major obstacle to the global malaria elimination campaign. Specific mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediate resistance to the 4-aminoquinoline drug chloroquine and impact parasite susceptibility to several partner agents used in current artemisinin-based combination therapies, including amodiaquine. By examining gene-edited parasites, we report that the ability of the wide-spread Dd2 PfCRT isoform to mediate chloroquine and amodiaquine resistance is substantially reduced by the addition of the PfCRT L272F mutation, which arose under blasticidin selection.

Two cap residues in the S1 subsite of a Plasmodium falciparum M1-family aminopeptidase promote broad specificity and enhance catalysis.

The aminopeptidase PfA-M1 is a key contributor to peptide catabolism in the human malaria parasite Plasmodium falciparum. PfA-M1 substrate specificity is shaped by the cylindrical S1 subsite, which accommodates the sidechain of the substrate P1 residue. At the top of the S1 subsite are two "cap" residues, E572 and M1034, that are positioned to influence S1 subsite specificity.

Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium.

Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound.

Bioactive Neolignans and Other Compounds from Magnolia grandiflora L.: Isolation and Antiplasmodial Activity.

Bioassay-guided fractionation of a methanol extract of Magnolia grandiflora against Plasmodium falciparum yielded two new (1 and 2) and six known (3 - 8) bioactive compounds. The structures of the new compounds were assigned by mass spectrometric and 1D- and 2D-NMR data. Known compounds were identified by comparison of H-NMR and MS data with literature data.

Antiplasmodial Sesquiterpenoid Lactones from Trichospira verticillata: Structure Elucidation by Spectroscopic Methods and Comparison of Experimental and Calculated ECD Data.

A dichloromethane extract of Trichospira verticillata from the Natural Products Discovery Institute was discovered to have good antiplasmodial activity (IC ∼5 μg/mL). After purification by liquid-liquid partition and C reversed-phase HPLC, four new germacranolide-type sesquiterpenoid lactones named trichospirolides A-D (1-4) were isolated. The structures of the new compounds were elucidated by analysis of their 1D and 2D NMR and MS data.

Fortunoids A-C, Three Sesquiterpenoid Dimers with Different Carbon Skeletons from Chloranthus fortunei.

Three dimeric sesquiterpenoids (1-3), fortunoid A (1) possessing a new carbon skeleton of rearranged lindenane dimer and fortunoids B (2) and C (3) representing the first example of the dimers of a lindenane and a eudesmane sesquiterpene, were isolated from Chloranthus fortunei. Their structures with absolute configurations were established by spectroscopic data and electric circular dichroism analysis. Their biosynthetic origins were also proposed.

Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure-Activity Relationships.

Inspired by the discovery of the antimalarial drug artemisinin from a traditional Chinese medicine (TCM), a natural product library of 44 lindenane-type sesquiterpenoids was assessed for activities against the Dd2 chloroquine-resistant strain of the malaria parasite Plasmodium falciparum. These compounds were mainly isolated from plants of the Chloranthus genus, many species of which are named "Sikuaiwa" in TCM and have long been used to treat malaria. The compounds consisted of 41 sesquiterpenoid dimers and three monomers, including the 12 new dimers 1-12 isolated from Chloranthus fortunei.

New potently bioactive alkaloids from Crinum erubescens.

Antimalarial bioassay-guided fractionation of the swamp lily Crinum erubescens led to the isolation of four compounds with potent antiplasmodial activity. Compounds 1 and 2 were determined from their spectroscopic data to be the known pesticidal compound cripowellin A and the known pesticidal and antiproliferative compound cripowellin B. 1D and 2D-NMR techniques were used to determine the identities of 3 and 4 as the new compounds cripowellin C and D.

Parallel inhibition of amino acid efflux and growth of erythrocytic Plasmodium falciparum by mefloquine and non-piperidine analogs: Implication for the mechanism of antimalarial action.

Despite the troubling psychiatric side-effects it causes in some patients, mefloquine (MQ) has been used for malaria prophylaxis and therapy, due to its activity against all Plasmodium species, its ease of dosing, and its relative safety in children and pregnant women. Yet at present there is no consensus on the mechanism of antimalarial action of MQ. Two leading hypotheses for the mechanism of MQ are inhibition of heme crystallization and inhibition of host cell hemoglobin endocytosis.

New Antiplasmodial Diterpenes from Gutierrezia sarothrae.

Bioassay guided fractionation of the MeOH extract of the plant Gutierrezia sarothrae (Asteraceae) using an assay for antiplasmodial activity against the drug-resistant Dd2 strain of Plasmodium falciparum led to the isolation of the two new diterpenes 3α-angeloyloxy-15-hydroxylabda-7,13-dien-16,15-olid-18-oic acid (1) and 3α-angeloyloxy-15-methoxylabda-7,13-dien-16,15-olid-18-oic acid (2). The structures of 1 and 2 were elucidated by interpretation of 1D and 2D NMR spectroscopic data, mass spectrometry, and comparison with the data of related compounds reported in the literature. Compound 1 exhibited moderate antiplasmodial activity with an IC50 values of 10.

Euphorbesulins A-P, Structurally Diverse Diterpenoids from Euphorbia esula.

Aqueous ethanol extracts of powdered twigs of Euphorbia esula afforded 16 new diterpenoids, named euphorbesulins A-P. These euphorbesulins included presegetane (1-3), jatrophane (4-14), paraliane (15), and isopimarane (16) diterpenoids as well as six known analogues. Compounds 1-3 represent a rare type of presegetane diterpenoid.

Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds.

The phloroglucinol mallotojaponin C (1) from Mallotus oppositifolius, which was previously shown by us to have both antiplasmodial and cytocidal activities against the malaria parasite Plasmodium falciparum, was synthesized in three steps from 2',4',6'-trihydroxyacetophenone, and various derivatives were synthesized in an attempt to improve the bioactivity of this class of compounds. Two derivatives, the simple prenylated phloroglucinols 12 and 13, were found to have comparable antiplasmodial activities to that of mallotojaponin C.

Antiplasmodial phloroglucinol derivatives from Syncarpia glomulifera.

Bioassay guided fractionation of a MeOH extract of the stem bark of Syncarpia glomulifera (Myrtaceae) led to the isolation of the two new phloroglucinol derivatives (±)-rhodomyrtosone F (1) and (±)-calliviminone I (2), the three known triterpenes, betulinic acid (3), ursolic acid-3-acetate (4), and ursolic acid (5), and 1-(2,4,6-trihydroxyphenyl)-1-hexanone (6). Compound 1 exhibited strong antiplasmodial activity, while compounds 2-4 were moderately active and 5 and 6 were inactive in this assay. The structures of 1 and 2 were elucidated based on analyses of their mass spectrometric data, 1D and 2D NMR spectra, and comparison with related compounds.

Antimalarial diterpenoid dimers of a new carbon skeleton from Aphanamixis grandifolia.

Chemical investigation into the minor constituents of Aphanamixis grandifolia yielded three new diterpenoid dimers, aphadilactones E-G (1-3) featuring a new carbon skeleton. Their structures and absolute configurations were fully established by comprehensive spectroscopic data analysis and ECD calculation. Discovery of another two new dimers (4 and 5) suggested the structure of recently reported aphanamene A to be re-investigated.

Amino acid efflux by asexual blood-stage Plasmodium falciparum and its utility in interrogating the kinetics of hemoglobin endocytosis and catabolism in vivo.

The endocytosis and catabolism of large quantities of host cell hemoglobin is a hallmark of the intraerythrocytic asexual stage of the human malaria parasite Plasmodium falciparum. It is known that the parasite's production of amino acids from hemoglobin far exceeds its metabolic needs. Here, we show that P.

Evidence for a Golgi-to-endosome protein sorting pathway in Plasmodium falciparum.

During the asexual intraerythrocytic stage, the malaria parasite Plasmodium falciparum must traffic newly-synthesized proteins to a broad array of destinations within and beyond the parasite's plasma membrane. In this study, we have localized two well-conserved protein components of eukaryotic endosomes, the retromer complex and the small GTPase Rab7, to define a previously-undescribed endosomal compartment in P. falciparum.

A naturally variable residue in the S1 subsite of M1 family aminopeptidases modulates catalytic properties and promotes functional specialization.

M1 family metallo-aminopeptidases fulfill a wide range of critical and in some cases medically relevant roles in humans and human pathogens. The specificity of M1-aminopeptidases is dominated by the interaction of the well defined S1 subsite with the side chain of the first (P1) residue of the substrate and can vary widely. Extensive natural variation occurs at one of the residues that contributes to formation of the cylindrical S1 subsite.

Characterization of a glycerophosphodiesterase with an unusual tripartite distribution and an important role in the asexual blood stages of Plasmodium falciparum.

Catabolism of glycerophospholipids during the rapid growth of the asexual intraerythrocytic malaria parasite may contribute to membrane recycling and the acquisition of lipid biosynthetic precursors from the host. To better understand the scope of lipid catabolism in Plasmodium falciparum, we have characterized a malarial homolog of bacterial glycerophosphodiesterases. These enzymes catalyze the hydrolysis of glycerophosphodiesterases that are generated by phospholipase-catalyzed removal of the two acyl groups from glycerophospholipids.

Engagement of the S1, S1' and S2' subsites drives efficient catalysis of peptide bond hydrolysis by the M1-family aminopeptidase from Plasmodium falciparum.

The M1-family aminopeptidase PfA-M1 catalyzes the last step in the catabolism of human hemoglobin to amino acids in the Plasmodium falciparum food vacuole. In this study, the structural features of the substrate that promote efficient PfA-M1-catalyzed peptide bond hydrolysis were analyzed. X-Ala and Ala-X dipeptide substrates were employed to characterize the specificities of the enzyme's S1 and S1' subsites.